Tears protect the eyes from many kinds of external stimuli. It is estimated that over 30% of people suffer from some type of ocular surface disease or disorder, many being classified as suffering from dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS). DES refers to an ocular affliction characterized by a dryness sensation in the eye often accompanied by grittiness, tearing, burning, blurred vision, or a foreign-body sensation. If left untreated, dry eyes can lead to more serious problems such as chronic dry eye syndrome, inflammation of the ocular surface and epithelial cell damage, or even blindness. It is generally accepted that dry eyes are caused by an abnormality in the quality or quantity of tears on the eye surface, such as tear imbalance, that could lead to a loss of proper lubrication and discomfort. The cause of these abnormalities can be an underlying medical condition such as Sjögren's syndrome, vitamin deficiencies such as vitamin A, rheumatoid arthritis, lupus, ocular rosacea, or other non-specific autoimmune or inflammatory disease. Other causes include bacterial infections of the eye, post-refractive surgery disruptions, allergic reactions, contact lens wearing, lid or blink anatomy abnormalities, neurological damage, and side effects from certain medications.
The tear film consists of three layers: the outer lipid layer, the middle aqueous layer, and the inner mucus layer. The lipid layer consists of oils exuded from over 20 meibomian glands that line the inner edge of the eyelid. The lipid layer is in contact with the air and functions to inhibit evaporation of tears. The middle layer is the aqueous layer and is produced by the lacrimal gland located above the upper outer portion of the globe within the orbit. The aqueous layer contains ions and macromolecules such as proteins. The mucus layer is between the aqueous layer and the ocular epithelial cells and is formed by the goblet cells located in the subconjunctival space. The primary function of the mucus layer is to help stabilize the tear film.
Aqueous tears are produced by the lacrimal glands and the conjunctiva, and those that remain in the eye can be evaporated or drained through the lacrimal canaliculi into the nose. A reduction in tear production or increase in tear elimination will often lead to dry eye. In addition, the lipid layer and the mucus layer play important roles in the dynamics of aqueous tears. For example, imperfections of the lipid layer can increase tear evaporation rates, and insufficient production of mucus can destabilize the tear film and lead to tear film disruption.
Dry eye syndrome has numerous causes typically associated with a deficiency in one or more layers of the tear film. In addition to the underlying diseases mentioned above, changes in steroid hormone levels have been implicated in causing dry eye syndrome. For example, dry eye is associated with the decline in estrogen, progesterone and testosterone levels in post-menopausal women. Furthermore, men on anti-androgen therapies for disorders such as hormone-dependent prostate cancer often suffer from dry eye (Krenzer et al., (2000) J Clin Endocrin & Metab, 85 (12): 4874-82.) Multiple studies on both human and rodent ocular gland tissues suggest the presence of estrogen, progesterone and androgen receptor mRNA and proteins in multiple ocular tissues including the lacrimal gland, lacrimal gland acinar epithelial cells, and meibomian gland. As described in U.S. Pat. No. 6,659,985, and US Patent Application Publications 200810132475 and 201010016264, topical therapies comprising the application of testosterone, estrogen, and/for progesterone directly to the eye or proximately to the eye have shown some efficacy in improving the symptoms of dry eye. Topical administration of these compositions in or near the eye can, however, cause further irritation, burning, or stinging in the eye, and the concentrations of the hormones used in these treatment methods are high enough such that systemic hormone exposure may be a concern.
Aqueous tear deficiency (ATD) is the most common cause of dry eye and is due to insufficient tear production from the lacrimal glands. Aqueous secretion from the lacrimal gland is generally controlled by the ophthalmic division of the trigeminal V1 nerve. This network of nerve fibers directly and indirectly controls tear formation in the lacrimal glands resulting from both reflexive responses such as a foreign body entering the eye and emotional responses. Structurally, these nerve fibers lie proximate to the surface of the skin, for example, at the forehead, temples, and the area just below the eyebrow.